The Clinical Genetics Branch (CGB) is NCI"s base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators. Hereditary Breast/Ovarian Cancer DCEG has been studying the Hereditary Breast/Ovarian Cancer (HBOC) syndrome since the 1960s; it now comprises a genetic disease paradigm for addressing vital translational research questions. We use a prospective cohort of 32 BRCA mutation-positive families with extensive clinical and epidemiologic information, and biological samples [NCI Protocol #02-C-0212]. 86 new mutation-positive families have enrolled during the past year. Research highlights include documenting a 62% reduction in breast cancer risk among women undergoing risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA mutation-positive families, a series of important positive, and definitive-negative candidate gene studies analyzing genetic modifiers of BRCA1/2-related breast cancer risk as part of the Consortium of Investigators of Modifiers of BRCA1/2 ("CIMBA") project, and a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment. The most noteworthy CIMBA-related findings include confirmation that RAD51 significantly modifies the risk of BRCA2-related breast cancer, and that FGFR2 and TNRC9 play important roles in the risk of BRCA-related breast cancer. Inherited Bone Marrow Failure Syndromes (IBMFS) Study The Inherited Bone Marrow Failure Syndromes (IBMFS) Program is our second major hereditary cancer project, led by Dr. Blanche Alter, a world-class clinical and laboratory investigator with a career-long interest in Fanconi anemia (FA) and related disorders, which all share a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and selected solid tumors. Her comprehensive, multidisciplinary protocol represents the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders [NCI Protocol #02-C-0054]. To date, 754 consented members from nearly 200 families have been enrolled. Major findings to date include refined, quantitative estimates of FA-related cancer risks, a model based on clinical phenotype which predicts the risk of critical FA outcomes (marrow failure, transplant, cancer and death), the first description of how bone marrow transplant amplifies the intrinsic excess risk of FA-related squamous cell cancers of the head/neck, an insightful, hypothesis-generating analysis of the bi-allelic mutations in BRCA2 which cause FANC-D1, the discovery that hyperlipidemia and osteoporosis are part of the FA clinical phenotype, a novel hypothesis regarding the pathogenesis of acute leukemia in patients with severe congenital neutropenia, and the high-impact discovery that very short telomeres represent a diagnostic test for dyskeratosis congenita. Familial Testicular Cancer The Familial Testicular Germ Cell Tumor study represents an inadequately-studied familial cancer disorder being evaluated under two new protocols, one accruing and evaluating a series of new multiple-case families (the "NCI Testicular Germ Cell Tumor " TGCT " Study") [NCI Protocol #02-C-0178], and a second, aimed at mapping and cloning new TGCT susceptibility genes, in collaboration with the International Testicular Cancer Linkage Consortium (ITCLC) [NCI Protocol #04-C-N076]. Through the former, we have enrolled 506 consented members (136 of whom have been evaluated at the NIH Clinical Center) from 100 newly-ascertained families. Findings from this multidisciplinary, etiologically-oriented family study include recognition that testicular microlithiasis is more common than expected in TGCT kindred, and tends to cluster in a sub-set of families (raising the possibility of a genetic predisposition to microlithiasis), the absence of constitutional cytogenetic abnormalities in the largest series of familial TGCT (FTGCT) patients yet reported, recognition of a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lipomas and lentigenes, and the absence of a dysmorphic phenotype in this disorder, which is thought to originate during intra-uterine development. We have contributed 389 DNA samples from 58 new FTGCT kindred to the gene discovery activities of the ITCLC, making us the second largest contributor to that collaboration. Observations reported from this effort include a genome-wide linkage screen of 295 multiple-case families which did not confirm the prior finding of a candidate locus on chromosome Xq27, but rather suggested that multiple low-penetrance genes acting in concert may underlie FTGCT, identification of the Y chromosome gr/gr deletion as the first genetic modifier of TGCT risk (both familial and sporadic) (55), exclusion of the mouse DND1 TGCT susceptibility gene as a candidate for human TGCT, and a descriptive analysis of 469 TGCT families (containing 1002 TGCT cases) in the ITCLC registry, which demonstrated surprising similarity between the characteristics of familial and sporadic TGCT, and an absence of readily-recognizable phenotypic family subsets. Other Familial Cancer Syndromes Familial Transitional Cell Carcinoma of the Urinary Tract (FTCCUT) represents another inadequately-studied familial cancer syndrome, one in which DCEG investigators have an historical interest. We have been exploring the possibility of launching a multidisciplinary, etiologically-focused study of this syndrome. We have submitted a literature review related to genetic determinants of urinary tract malignancy. For the moment, further development of this project is on hold, due to concerns that there simply may not be a sufficient number of high-risk families available for study. Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of CGB"s research portfolio, although it has not been designated as an official Program. During the past 4 years, 21 manuscripts have been published, and an additional 5 are currently under review. Manuscripts now being completed include analyses of complementary and alternative medication use in women from BRCA1/2 mutation-positive families; testicular self-examination practices in at risk members of FTC kindred; and family communication patterns in HBOC families (a social network analysis). Ongoing analyses are comprised of validation of our predictive model of choosing between surgery and screening among women at increased risk of ovarian cancer; baseline quality of life among GOG-199 study participants; ambiguity related to breast/ovarian cancer screening test outcome as a modulator of mood and screening behavior; determinants of bone marrow transplant decision-making among Fanconi anemia family members; CEGRM assessment among men at increased cancer risk; and patterns of general cancer screening behavior among FTC family members (Jennifer Loud). We have demonstrated the feasibility and value of performing this type of study as an integral part of our clinical research protocols. Future research will build upon findings from current studies, at a pace influenced by our ability to recruit a tenure-track investigator with appropriate expertise. Finally, we are developing a mindfulness-based, stress reduction program aimed at reducing stress and modifying related biomarkers among BRCA1/2 mutation-carriers.